The long-term objectives of this project are to elucidate the mechanisms involved in the adaptation of calcium (Ca) metabolism to the increased Ca demands of reproduction and the neonatal period. Past results have already stimulated clinical studies on the changes in the circulating concentration of the Ca regulating hormones in lactating women, as well as studies on intestinal Ca absorption in very low-birthweight infants. Future studies should be similarly provocative. Specific aims concerning the regulation of intestinal Ca absorption during reproduction include the identification of factors responsible for the periparturient peak of duodenal active Ca transport between 20 days of pregnancy and day 4 of lactation in rats. The potential role of 1,25-(OH)2D3, prolactin, placental lactogen-II, estrogen, or parathyroid hormone-related peptide (PTHrP) will be evaluated by varying the serum levels of these hormones in pregnant rats. Changes in the Ca transport ratio (serosal/mucosal, using everted gut sacs), the concentration of duodenal calbindin-D9k and its messenger RNA, and the duodenal 1,25-(OH)2D3 receptor will be measured. Nonsaturable Ca absorption in the jejunum and ileum will be determined during the periparturient period, in order to extend our earlier work indicating enhanced efficiency of nonsaturable calcium absorption in late lactation. Specific aims regarding regulation of parathyroid hormone (PTH) secretion during lactation will include elucidating why superphysiolgic serum Ca levels do not suppress serum PTH levels of lactating rats to the same extent as in nonlactating rats. A bone cell CAMP bioassay will be used to study the pattern of Ca suppression of PTH release from dispersed rat parathyroid cells, and to determine if there is a unique (relationship between extracellular and intracellular Ca concentrations in lactating rats, perhaps due to an action of corticosterone, which circulates at high levels during lactation. Specific aims on regulation of synthesis of 1,25-(OH)2D3 in lactating and suckling rats include determining if the rise in circulating 1,25-(OH)2D3 levels at the end of pregnancy and the fall at 1-2 days of lactation are caused by parallel changes the rate of renal biosynthesis of the hormone as determined by the activity of the renal 25-OHD-1-OHase, and if the pregnancy-related increase could be due to an effect of hypocalcemia, PTH, placental lactogen-II or estrogen on the 1 -OHase, or to an increase in placental 25-OHD-1-OHase that may be stimulated by parathyroid hormone-related peptide (PTHrP). Experiments will also reveal if extrarenal synthesis of 1,25-(OH)2D3 occurs in lactation, perhaps by the mammary gland in response to a paracrine action of PTHRP.